The overall objective of the Genetic Analysis of Idiopathic Thrombosis (GAIT) project is to identify genetic -influences on susceptibility to thrombosis through genetic analysis of quantitative risk factors related to disease, including plasma levels of components of the hemostatic and fibrinolytic pathways as well as functional measures of protein activity and blood clotting efficiency. The GAIT sample includes 396 individuals in 21 multigenerational Spanish families for whom quantitative and diagnostic phenotypes are available as well as genotypes for a 10 cM genome scan. Analyses in the GAIT sample have previously documented the strong heritabilities of many of the quantitative measures of hemostasis and fibrinolysis, identified which of these risk factors share pleiotropic genetic influences with liability to thrombosis, and localized quantitative trait loci (QTLs) influencing some of these traits. In this grant application, we propose to follow-up three of the most promising linkage results from the full genome screen using a combination of standard fine-mapping techniques, joint analyses of linkage and linkage disequilibrium, and a newly developed method, called quantitative trait nucleotide analysis, to evaluate positional candidate genes within regions of linkage. The three linkage signals to be pursued include two QTLs for plasma levels of factor XII, one on chromosome 5q with a LOD score of 10.21 and one on chromosome lop with a LOD core of 3.53, and a QTL for tissue factor pathway inhibitor on chromosome 2q (LOD score = 3.52). The specific aims of the proposed research are: 1) to determine whether the factor XII structural gene (FXJ1) is the previously detected QTL on chromosome 5 influencing plasma levels of factor XII; 2) to determine whether the tissue factor pathway inhibitor structural gene (TFPI) is the previously detected QTL on chromosome 2 influencing plasma levels of TFPI; and 3) to refine and confirm a linkage signal for plasma levels of factor XII on chromosome 10 in a region containing no known positional candidate genes.